White blood cells called T lymphocytes play critical roles in immune defense against viruses, bacteria, fungi, protozoa, and cancer cells. They are also involved in allergies / asthma due to the development of an unwanted or excessive type of immune response to substances in our environment and in autoimmune diseases that result from the inappropriate attack of these cells on the body's own tissues. T cells develop in a gland called the thymus, where they learn to distinguish the natural components of the body from the mutant proteins in tumor cells or those produced by infectious agents. This education process involves allowing cells with useful forms of surface proteins called receptors to mature into functional T cells and eliminating cells with inappropriate receptors before they can become dangerous. This process must work properly to generate the set of T cells needed for effective responses to invading organisms and cancer, without allowing development of those cells harmful to normal body tissues. One goal of our work is to understand how this "education / selection" process occurs and the stages through which the maturing T cells pass. Because T cells see foreign substances (antigens) in the form of peptide-major histocompatibility complex (MHC) molecule complexes on cell surfaces, we also wish to know how such materials interact with the T cell receptor to guide the development of T cells in the thymus and the activities of mature T cells in the body. A careful re-examination of the generally accepted scheme of thymocyte development has led us to propose a new model that more fully explains a number of discrepancies among previously published studies and that provides new insight into the signals required for effective development of a mature T cell. We have also determined that a large number of T cells that could potentially mature (as many as half) are killed within the thymus at a late stage of development. This finding has importance for understanding the potential errors in tolerance induction that may underlie autoimmune disease.